2-Chloroanthraquinone-catalyzed aerobic photo-oxidative synthesis of diacylamines from benzylamides

Article abstract of DOI:10.1016/j.tetlet.2014.03.123

In this Letter, we report the aerobic photo-oxidative synthesis of diacylamines from benzylamides in the presence of molecular oxygen and catalytic amounts of 2-chloroanthraquinones under visible light irradiation from a fluorescent lamp.

Full text of DOI:10.1016/j.tetlet.2014.03.123

Tetrahedron Letters 55 (2014) 3146–3148
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
2-Chloroanthraquinone-catalyzed aerobic photo-oxidative
synthesis of diacylamines from benzylamides
Izuho Itoh a, Yoko Matsusaki a, Akitoshi Fujiya a, Norihiro Tada a, Tsuyoshi Miura b, Akichika Itoh a,
⇑
a Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
b Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, we report the aerobic photo-oxidative synthesis of diacylamines from benzylamides in the
presence of molecular oxygen and catalytic amounts of 2-chloroanthraquinones under visible light irra-
diation from a fluorescent lamp.
Received 27 January 2014
Revised 24 March 2014
Accepted 28 March 2014
Available online 4 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Aerobic
Anthraquinone
Diacylamine
Photo-oxidation
Visible light
Diacylamines are important structural motifs as starting
materials for the preparation of N-containing heterocycles such
as triazoles,1 oxazols,2 and imidazolins.3 Furthermore, diacylam-
ines have also been studied from the viewpoint of biological activ-
ity.4 In general, the preparation of diacylamines involves the
acylation of amides with carboxylic acid anhydrides,5 acyl chlo-
halogen reagents remains an obstacle to the development of a
more environmentally benign method. Recently, we have studied
photo-oxidative reactions with organo-photocatalysts such as
anthraquinones.22 Here we report our detailed study of the aerobic
photo-oxidation of benzylamides to the corresponding diacylam-
ines under visible-light irradiation in the presence of an organop-
hotocatalyst (Scheme 1).
To explore this approach, we selected N-benzylacetamide (1a)
as a test substrate to optimize the reaction conditions (Table 1).
Among the solvents and catalysts irradiated with a fluorescent
lamp under an oxygen atmosphere (entries 1–13), ethyl acetate
in combination with 2-chloroanthraquinone (2-Cl-AQN) provides
N-acetylbenzamide (2a) most efficiently (entry 4). Addition of base
and acid resulted in a slight reduction in the yield (entries 14 and
15). Reducing of the catalyst-loading to 0.05 equiv gave lower yield
of 2a (entry 17). Furthermore, increasing of the catalyst-loading to
0.2 equiv also resulted in lower yield probably because of low sol-
ubility of 2-Cl-AQN in ethyl acetate (entry 18). Finally, prolonging
the reaction time to 30 h gave the best result (entry 16). Notably,
2-Cl-AQN, visible-light irradiation, and molecular oxygen are nec-
essary for this reaction because 2a cannot be satisfactorily
rides,4,6 ketenes,7
a,a,a
-trichloromethyl carbonyl compounds,8 or
enol esters;9 however, these methods suffer from various draw-
backs such as low product yields, strong environmental impacts
of the solvents used, or wastes produced. Other methods for the
synthesis of diacylamines is oxidation of amides, which using tran-
sition metal catalysts (Ru,10 Cr,11 Cu,12 Co,13 Mn,14 Fe,15 Ag/Cu16
)
combined with stoichiometric reoxidants. On the other hand,
metal-free oxidation of amides with stoichiometric amounts of
organic reagents such as DMP,17 tert-butylperoxyiodane,18 and
DDQ19 has been reported to date. From these perspectives, we have
studied oxidation processes based on the use of molecular oxygen,
and have observed that benzylamides were oxidized to the corre-
sponding diacylamines successfully under external photoirradia-
tion in the presence of catalytic amounts of iodine20 or HBr.21
Although these methods are interesting from a green chemistry
perspective due to the non-use of heavy metals, waste reduction,
the use of molecular oxygen, the use of inexpensive reagents,
and the use of environmentally low-impact solvents, the use of
O2, hν (fluorescent lamp)
O
O O
cat. 2-Cl-AQN
EtOAc
Ar
N
H
R
Ar
N
R
H
⇑
Corresponding author. Tel.: +81 58 237 3931; fax: +81 58 237 5979.
E-mail address: itoha@gifu-pu.ac.jp (A. Itoh).
Scheme 1. Aerobic photooxidative synthesis of diacylamines.
http://dx.doi.org/10.1016/j.tetlet.2014.03.123
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

I. Itoh et al. / Tetrahedron Letters 55 (2014) 3146–3148
3147
Table 1
Table 2
Study of reaction conditionsa
Aerobic photooxidative of diacylaminesa
O
O2, hν (fluorescent lamp)
O
O
O2, hν (fluorescent lamp)
catalyst
2-Cl-AQN (0.1 equiv)
N
H
1a
N
H
substrate
product
solvent, rt, 10 h
EtOAc, rt
2a
Entry
1
Substrate
Product
Time (h)
30
Yieldb (%)
Entry
Catalyst (equiv)
AQN (0.1)
Solvent
Yieldb (%)
O
O
O
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
Hexane
iPr2O
61
66
0
88
85
6
N
H
1a
N
H
2a
88 (76)c
93
2-tBu-AQN (0.1)
1-Cl-AQN (0.1)
2-Cl-AQN (0.1)
AQN-2-CO2H (0.1)
Anthracene (0.1)
Benzophenone (0.1)
Methylene blue (0.1)
2-Cl-AQN (0.1)
2-Cl-AQN (0.1)
2-Cl-AQN (0.1)
2-Cl-AQN (0.1)
2-Cl-AQN (0.1)
2-Cl-AQN (0.1)
2-Cl-AQN (0.1)
2-Cl-AQN (0.1)
2-Cl-AQN (0.05)
2-Cl-AQN (0.2)
—
O
O
N
H
N
H
2
3
4
5
6
7
8
9
30
20
50
20
30
30
30
30
Cl
Cl
1b
2b
O
2
1
O
O
O
Trace
0
13
75
0
N
H
1c
N
H
2c
82
t-Bu
MeO
t-Bu
MeO
CHCl3
AcOH
H2O
O
O
N
H
1d
N
83
H
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
81c
86d
95e
49
76
0
2d
O
N
H
O
O
N
99
H
Ph
Cl
Ph
Cl
1e
2e
O
O
O
2-Cl-AQN (0.1)
2-Cl-AQN (0.1)
2-Cl-AQN (0.1)
0f
N
H
N
H
26g
73h
81
1f
2f
a
O
O
O
Reaction conditions: 1a (0.3 mmol) and catalyst in solvent (3 mL) were stirred
N
H
1g
N
H
and irradiated externally with a fluorescent lamp under oxygen atmosphere at
room temperature for 10 h.
30
80
71
2g
O
N
H
1H NMR yields.
b
O
O
c
The reaction was carried out with K2CO3 (0.1 equiv).
The reaction was carried out with AcOH (0.1 equiv).
The reaction was carried out for 30 h.
The reaction was carried out in the dark.
The reaction was carried out under argon.
The reaction was carried out under air.
d
N
H
e
1h
2h
O
f
O
O
g
N
H
O
N
H
O
h
1i
2i
O
O
O
N
H
1j
Ph
N
H
2j
Ph
10
11
70
70
74
0
obtained without them (entries 19–21). Interestingly, this reaction
proceeded in good yield, even under an air atmosphere (entry 22).
Table 2 shows the scope and limitations of this oxidation pro-
cess under the aforementioned optimized reaction conditions.23
N-Benzylacetamides that possess an electron donating or
withdrawing group at their aromatic nucleus, produce the
corresponding diacylamines in high to excellent yields (entries
1–6). N-(1-Naphthylmethyl)acetamide (1g) produced the
corresponding product (2g) in only 30% yield (entry 7). N-Benzyl-
3-methylbutylamide (1h), N-(phenylmethyl)-1,1-dimethylethyl
ester carbamic acid (1i), and N-benzylbenzamide (1j) were
converted into the corresponding diacylamines in good yields
(entries 8–10). Unfortunately, N-dodecylacetamide (1k), an
aliphatic amide, was intact under these conditions (entry 11). It
should be noted that this reaction can easily be performed on a
3 mmol scale to give 2a in 76% yield without further optimization
(entry 1).
Scheme 2 shows a plausible mechanism for this oxidation. The
proposed mechanism takes into account the necessity of continuous
irradiation, a catalytic amount of 2-Cl-AQN, and molecular oxygen
for this reaction. The amide initially reacts with AQN⁄, which is gen-
erated from AQN by irradiation with a fluorescent lamp,24 to give
benzyl radical species 3. The radical species 3 trap molecular oxygen
to afford peroxyradical 4, which is subsequently transferred to
hydroperoxide 5 by abstraction of a hydrogen radical from 1 or
AQH. A diacylamine 2 is formed through dehydration from 5.
O
O
O
N
N
10 H
10 H
1k
2k
a
Reaction conditions: 1 (0.3 mmol) and 2-Cl-AQN (0.1 equiv) in ethyl acetate
(3 mL) were stirred and irradiated externally with a fluorescent lamp under oxygen
atmosphere at room temperature.
b
Isolated yields.
c
Compound 1a (3 mmol) and 2-Cl-AQN (0.1 equiv) in ethyl acetate (30 mL) were
stirred and irradiated externally with a fluorescent lamp under oxygen atmosphere
at room temperature for 15 h.
hν
AQH
AQN
AQN
Ph
AQN*
AQH
O
O
O2
Ph
Ph
N
H
3
N
H
1
O
O
OH
O
O
H
O
O
N
Ph
Ph
N
H
H
H
5
4
O
N
H
2
Scheme 2. Plausible reaction mechanism.

3148
I. Itoh et al. / Tetrahedron Letters 55 (2014) 3146–3148
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preparation of diacylamines by the aerobic photo-oxidation of
amides in the presence of the catalytic amount of 2-Cl-AQN under
visible-light irradiation. This oxidation is a facile and convenient
method from the viewpoint of synthetic organic chemistry and is
relevant from a green chemistry perspective.
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Acknowledgments
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This work was supported by Grant-in-Aid for Young Scientists
(B) (No. 24790015) from the Japan Society for the Promotion of Sci-
ence (JSPS).
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22. (a) Tada, N.; Hattori, K.; Nobuta, T.; Miura, T.; Itoh, A. Green Chem. 2011, 13,
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Tetrahedron Lett. 2013, 54, 162–165; (c) Matsusaki, Y.; Yamaguchi, T.; Tada, N.;
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23. A typical procedure (entry 1) follows: A dry EtOAc solution (3 mL) of the N-
benzylacetamide (1a, 0.3 mmol), 2-Cl-AQN (0.03 mmol) in a pyrex test tube
equipped with an O2 balloon, was irradiated for 30 h with four 22 W
fluorescent lamps, which were set up at a distance of 65 mm. The reaction
mixture was concentrated under reduced pressure, and the pure product was
obtained by preparative TLC or flash silicagel chromatography.
24. 2-Chloroanthraquinone absorbs light of wavelengths shorter than 450 nm, and
the fluorescent lamp radiates visible light of wavelengths longer than 400 nm.
Thus, 2-chloroanthraquinone absorbs light between 400 and 450 nm.
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